Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide, accounting for 32% of all deaths in 2019 (17.9 million). In addition, this disease can cause serious sequelae that reduce quality of life and life expectancy, requiring the implementation of public health measures to prevent its occurrence.

The pathophysiology of this condition is complex, involving multiple factors that are intertwined in both space and time. Atherosclerotic disease originates in the arterial tree, in areas where shear stress causes activation of the endothelium lining the arterial wall (Wentzel et al., 2012). The increased permeability of the endothelium, particularly at arterial bifurcations, allows circulating atherogenic lipoproteins to enter the subendothelial space where they can be trapped, leading to cholesterol accumulation in the arterial intima. This phenomenon is accompanied by the induction of a local inflammatory state and the recruitment of immune cells to sites of injury (Moore, Sheedy, & Fisher, 2013).

Macrophages, which are mainly derived from blood monocytes, play a central role in atherogenesis. In particular, they are involved in the removal of trapped lipoproteins, such as low-density lipoproteins (LDL) in modified form, from the arterial wall and equally in the apolipoprotein A1 (ApoA1)-mediated reverse transport of cholesterol to the liver. Due to their inflammatory environment, lipoproteins located in the subendothelial space are subject to various enzymatic and oxidative modifications in the arterial intima (Boren et al., 2020). As a result, these modified lipoproteins are no longer recognized by their classical cellular receptors, leading to dysregulation of their uptake by macrophages and inducing intracellular cholesterol accumulation. In addition, the presence of dysfunctional oxidized forms of ApoA1 in atherosclerotic plaques may limit the cholesterol efflux and accentuate intracellular cholesterol accumulation in macrophages (Huang et al., 2014). The generation of macrophage-derived cholesterol-laden cells, called foam cells, is a milestone in the formation of atherosclerotic plaques (Chistiakov, Melnichenko, Myasoedova, Grechko, & Orekhov, 2017). Indeed, cholesterol accumulation in the intima, together with persistent inflammation, leads to extracellular matrix remodeling events, with the migration of vascular smooth muscle cells from the media into the intima, and the formation of a fibrous cap surrounding a lipid core (Linton et al., 2016). This process can continue for years before causing a reduction in the arterial lumen and provoking clinical symptoms. The development of intense inflammatory and apoptotic processes within the plaque, associated with defective macrophage efferocytosis, can also lead to increased cell necrosis and the formation of a necrotic core, significantly increasing the risk of plaque rupture (Bentzon, Otsuka, Virmani, & Falk, 2014).

Therapeutic approaches to attenuate ASCVD are mainly based on lipid-lowering strategies, either through lifestyle changes or the introduction of pharmacological treatment. However, the persistence of a residual cardiovascular risk requires the development of new therapies to prevent the occurrence of such adverse events. The aim of this review is therefore to discuss alternative therapeutic strategies and, in particular, the value of targeting mitochondrial function in macrophages. We will therefore focus on the relationship between mitochondrial dysfunction and atherosclerotic plaque progression, how the atheroprotective functions of macrophages depend on mitochondrial metabolism, and the therapeutic potential of improving mitochondrial function in macrophages in ASCVD.